1. Field of the Invention
This invention relates to improved means of intravascular, intraparenchymal and intracerebroventricular delivery of agents such as diagnostic agents or therapeutic agents for the treatment of local medical conditions in the head and body. Such treatments and local medical conditions may include, by way of non-limiting examples, neoplasms, the counteraction of neurodegenerative disorders, the recanalization and reperfusion of blocked arterial and venous structures and the treatment of other forms of disease within the vasculature and elsewhere in the body. Systemic delivery of therapeutic agents into the brain is limited by the presence of the blood brain barrier formed by the tight junctions of endothelial cells that line capillaries within the brain. As a result, many diseases and disorders of the central nervous system are inadequately treated by conventional systemic therapies. The search for new approaches for dealing with this problem has lead to the development of positive pressure infusion as a means for delivering therapeutic agents directly into the brain, thereby bypassing the blood brain barrier. A general requirement for targeted delivery of therapeutic drug agents, gene vectors and cells into the brain parenchyma, cerebral fluid compartments or cerebral vasculature is the availability of suitable access devices. The present invention relates to the field of acute or chronic implantable medical devices and catheters in particular. More specifically, the invention relates to a class of catheters that can be used to carry out positive pressure infusions of therapeutic agents into an organ, particularly a solid tissue organ such as a brain, for the purpose of avoiding the restrictive effects of the blood-brain barrier. The invention additionally relates to a class of catheters that can be used to deliver fluids into or remove fluids from within the vasculature of a body. The invention also relates to that class of catheters that are multi-lumen devices. The invention further relates to classes of treatment that may utilize successive delivery of initial and follow-up doses of therapeutic agents, or successive delivery of a first and then subsequent different therapeutic agents, into the same location or set of locations within a body part of a patient or live being such as a brain or a tubular vascular structure of an animal or human being.
2. Background of the Art
There are many instances in which a neurosurgeon, an interventional radiologist, a cardiologist or other clinician would wish to deliver a diagnostic or therapeutic agent into a targeted local area, especially the brain, the cerebral vasculature, the cardiovascular system or elsewhere in the vasculature or the body ducts of a patient, for example, for the treatment of a local condition, such as neoplastic disease or arterial blockages. Potential therapeutic applications for the delivery of such agents would include but not be limited to the delivery of chemotherapeutic and antiangiogenic agents for the treatment of glioblastoma multiforme and other intracranial neoplasms, the delivery of angiogenic drug and gene agents and autologous stem cells into the heart to reverse tissue damage following myocardial infarcts, and the delivery of antithrombolytic agents into the peripheral vasculature to break up thrombotic and stenotic occlusions and allow for recanalization of arteries and veins and reperfusion of dependent tissues. To enlarge upon one of these applications, consider that positive pressure infusion of agents directly into the bulk brain tissues is a technique that has been taught by several workers, examples of which are Laske, et al., (U.S. Pat. No. 5,720,720), Kucharczyk, et al., (U.S. Pat. No. 6,026,316), and Gillies, et al., (U.S. Pat. No. 6,272,370). The resulting convection-enhanced flow of catheter-delivered infusates through the interstitial space of the brain can provide for regional volumes of distribution of therapeutic agents without the need to have large molecular weight species traverse the blood-brain barrier. Special neurocatheters optimized for this approach to drug delivery are needed in order to maximize the utility of such therapies. This general approach to intraparenchymal therapies also applies to the delivery of autologous stem cells into tissues in the brain and heart for the treatment of neurodegenerative disorders and the sequellae of myocardial infarction, respectively, as well as for infusion protocols for the assessment and treatment of traumatic brain injury.
Specialized multi-lumen therapy-delivery catheter systems have been disclosed by Kucharczyk et al. in U.S. Pat. No. 6,626,902 and in European Patent Application No. 01303108.3-2310. Coaxial catheters for the intraparenchymal delivery of cells and drug agents have been disclosed by Kucharczyk et al. in U.S. Pat. No. 6,599,274 and U.S. patent application Ser. No. 10/444,884 and Gillies has disclosed a catheter means with adjustable port holes for control of regulation of the flow of infused agents into the brain, in U.S. Ser. No. 60/380,387 (abandoned, now 60/645,302). Several clinical and pre-clinical applications of various types of therapy delivery catheters are discussed in the articles of Chen, Z.-J., et al., “Intraparenchymal Drug Delivery via Positive Pressure Infusion: Experimental and Modeling Studies of Poroelasticity in Brain Phantom Gels,” IEEE Transactions on Biomedical Engineering, 49 (2), 85-96, (February 2002); Broaddus, W. C., et al., “Advances in Image-Guided Delivery of Drug and Cell Therapies into the Central Nervous System,” Neuroimaging Clinics of North America, 11 (4), 727-735, (November 2001); and Broaddus, W.C., et al., “Strategies for the Design and Delivery of Antisense Oligonucleotide in Central Nervous System,” Methods in Enzymology: Antisense Technology, Part. B: Applications, 314, 121-135 (2000).
One limitation of the art is that none of the catheters known to have been developed to date, nor many others of those foreseen in the literature have been optimized in design for the localized control of dwell time of delivered agent during a targeted delivery. The dwell time refers to the time (actually a concentration over time) for which the agent remains at a satisfactorily active level at the location where it is intended to be active. In particular, there has been no optimization of recirculation of the infused agent in ways that do not damage the adjacent tissues if the agent is being delivered intraparenchymally, or in ways that do not restrict blood flow if the agent is being delivered inside the vasculature. This would be a desirable feature, especially in instances where the infusate might otherwise simply be carried away by the local flow of blood, thus permitting only a limited dwell-time of it in the target zone of interest. Among those catheters claiming some form of recirculative capabilities is that described by Evans et al. (U.S. Pat. No. 6,663,613) which teaches a certain method of rotary arterectomy that might be carried out in concert with the recirculation of antithrombolytic agents within the lumen of a blood vessel. The technique is limited in that balloons, filters or other shielding means must be positioned on either side of the recirculation zone in order to contain the agent. The blockage of local blood flow cannot be tolerated indefinitely, nor can such means be extended into solid tissues of the brain without damage to those tissues. The device described by Barbut (U.S. Pat. No. 6,312,444) suffers from a similar limitation. The system of Heruth (U.S. Pat. No. 6,198,966) is further limited in that once the agent exits the distal tip of the catheter, it cannot recirculatively return into it, even though the flow of the agent within the catheter can circulate internally through the device in a continuous manner. A still further-related limitation is that found in the catheter of Wernerth et al. (U.S. Pat. No. 6,379,378) in which the recirculative flow of a working fluid inside the catheter is able to modulate the temperature-dependent performance characteristics of a urokinase antithrombolytic agent, but without the agent itself being able to recirculate through the catheter in order to re-treat a region of vascular stenosis.
A second limitation of the existing art is that many types of multi-lumen implantable devices that are suitable, e.g., for recirculative hemodialysis are nevertheless not configured in such a way that a given volume of therapeutic agent could recirculatively flow into and out of a user-selected region in the distal tip of the device. This limitation applies to the devices disclosed in U.S. Pat. Nos. 5,624,413 (Markel et al.); U.S. Pat. No. 5,718,692 (Schon); U.S. Pat. No. 5,776,111 (Tesio); U.S. Pat. No. 5,947,953 (Ash et al.); and U.S. Pat. No. 6,638,242 (Wilson et al.).
A third limitation of the art is that the existing multi-lumen catheter designs do not describe pumping means for coordinately controlling emitting flow and recapture flow of agents, such as would enabling recirculative flow between the outside of an outermost lumen and the inside of an interior or innermost lumen. This is the case, for instance, in the device disclosed by Fleming (U.S. Pat. No. 5,718,678). In those cases where the existing multi-lumen catheter designs do allow for at least dialysis-like exchange of fluids between an outer lumen and tissues external to it, they would still be essentially nonfunctional in situations where there was substantial flow of a fluid around the outer lumen, as when the catheter is inserted into a blood vessel. Such a limitation applies for instance to the device disclosed by Odland (U.S. Pat. No. 6,537,241). A still further example of a related limitation is that suffered by the device of Hanson et al. (U.S. Pat. No. 5,709,874) which is able to deliver an agent into the boundary layer of the flow occupying the region between the inner lumen of the blood vessel and the vessel wall, but which is not able to recirculate the agent in order to increase its dwell time in the boundary layer region.
A fourth limitation in certain classes of the existing art is that the intra-tube flow dividers inside of some types of multi-lumen devices seals at the end of the catheter in such a way that there cannot be communication between the input and output channels. This is the case in the blood recirculation catheter of Siegel et al. (U.S. Pat. No. 6,409,700).
A fifth limitation of the existing art is that in catheters incorporating either active or passive flow control devices in their distal tips, the pressure gradients that are established are such as to preclude efficient recirculative flow. An example of the former is the device and system of Brisken (U.S. Pat. No. 6,228,046) and an example of the latter is that described by Schneiter (U.S. Pat. No. 6,533,763). A further limitation of passive flow control devices is that which arises in the device disclosed by Christensen et al. (U.S. Pat. No. 6,645,183) in which the length of the catheter alone is used to control the flow rate at a constant pressure, but no provision is made for recirculating the flow in the distal region of the device.
Another limitation in the prior art is that single port catheters provide only limited distribution of drugs because the effective radius of drug penetration of the drug agent is restricted. Attempts to overcome this problem by increasing the volume rate of delivery of the drug through a single port can result in unintended damage to brain cells and nerve fibers. Another aspect of this invention, therefore, is to overcome the inherent agent distribution limitations of single point drug delivery by devising a multi-lumen catheter with multiple drug release sources which under positive pressure delivery effectively disperse over an appropriate tissue region containing receptors for the drug agent.
Further examples of prior art in the field of the invention include U.S. Pat. No. 6,663,596 (Griego et al.), which discloses a coaxial catheter means for mixing chemical species in the distal tip of the catheter means in preparation for delivery of it into a body part through the catheter means, but not in a recirculative fashion; U.S. Pat. No. 6,834,201 by Gillies et al., discloses a coaxial catheter means in which there is a reversing flow from the inner tube to the outer tube, within the distal tip of the catheter means but not in a recirculative fashion relative to fluids in regions exterior to the distal tip of the catheter means; and Humphrey et al., “Hydrodynamically Unstable Turning Flow in the End-Space of a Magnetically Guided CNS Catheter,” in Kasagi, N., Eaton, J. K., Friedrich, R., Humphrey, J. A. C., Leschziner, M. A., and Miyauchi, T., eds., Proceedings of the Third International Symposium on Turbulence and Shear Flow Phenomena (Tokyo Institute of Technology, Tokyo, 2003), pp. 811-816, who describe the fluid dynamics of the reversing flow that occurs in one embodiment of the device disclosed by Gillies et al. in U.S. Pat. No. 6,834,201, but who also do not describe a recirculative therapy delivery system.
None of the multi-lumen intraparenchymal therapy delivery devices extant in the art overcome these limitations, nor does the prior art describe means, techniques, and systems for improving the designs of them such that these limitations would not prevent successful therapeutic protocols from being carried out.
There are numerous catheter designs that contain multiple lumens for parallel or adjacent flow of liquids, but none are believed to address capture and recirculation of materials for redlivery. For example, U.S. Pat. No. 6,758,828 (Hammer) describes an apparatus that delivers an agent to a treatment region, the apparatus having an outer cannula or lumen that has an internal surface and an external surface, the external surface being substantially smooth to penetrate tissue whereas the distal end is tapered; an inner cannula, or lumen coaxial to the outer cannula, providing a common fluid path (that is the same fluid passes through both the inner cannula and outer cannula) at the distal end with the inner surface of the outer cannula; a source of fluid to be passed through the common fluid path, the source of fluid comprising at least a reservoir of nutrients and/or gases for maintaining cells contained in a lumen coaxial and internal to the inner cannula; a semipermeable membrane comprises the surface of the lumen, thus allowing controlled material transport across the lumen surface; a source of cells or other biologically active material mass flow connected to the proximal lumen so that the cells or other biologically active material can exit the distal portion upon entering the target tissue; and a first flow distributor located at the proximal end of the outer cannula to provide substantially uniform flow through the outer cannula.
U.S. Pat. No. 6,030,358 (Odland) describes an apparatus having a pump reservoir and one or more microcatheters, for use in delivering and/or recovering fluid to and/or from a tissue site or for performing tissue engineering outside of the body.
Significant and potentially useful advances in the treatment of intracranial neoplasms, traumatic brain injury, neurodegenerative disorders, sequellae from myocardial infarcts, and coronary and peripheral vascular diseases could be realized if alternatives to the prior art were to be able to demonstrate safety and efficacy via improvement of the catheter systems used for recirculative delivery of therapeutic agents. The present invention discloses a means, technique, and system for attempting to reach this goal by implementation of a novel set of catheter means that traverse the limitations of the existing art discussed above.